A search using the PICO criteria yielded three RCTs relevant for the subject of mesh fixa-tion in endoscopic TEP-repair. All three studies included only patients with inguinal hernia’s. No studies were available on femoral hernias. The study of Buyukasik (2017) compared laparoscopic TEP inguinal repair using mesh with (seven metal spiral Tackers; n=50) and without fixation (n=50). Only male patients were included.

Claus (2016) studied TEP inguinal repair using mesh with and without fixation. In the mesh-fixation group 10 patients were included, the non-fixationgroup consisted of 50 patients. The study was said to be computer-randomized.

The study of Ayyaz (2015) also studied TEP inguinal repair with mesh fixation (n=32) and without mesh fixation (n=31). Follow-up was five years. No information was available on randomization, allocation concealment, loss to follow-up or intention-to-treat analysis.

Results

Chronic pain (critical outcome)

Two studies reported outcomes on chronic pain. The study of Ayyaz (2015) did report a mean chronic pain score (Visual Analogue Scale): 4.7 (±0.638). They did not specify the time-window of the score. Therefore, we could not use these outcomes. Buyukasik (2017) reported chronic pain scores after 1, 6 and 12 months, using the Numering Rating Scale (0 = no pain; 10 = most severe pain). After 1 month, the chronic pain score was 1.5 in the TEP with mesh fixation (±1.2) and 0,3 (±0.8) in the TEP group without fixation (p-value = 0.001). After 6 months, the scores were 0,8 (±1.6) in the fixationgroup and 0.4 (±0.7) in the non-fixationgroup (p-value = 0.109); after 12 months, the scores were 0.5 (±0.8) in the fixationgroup and 0,3 (±0.6) in the non-fixationgroup with a p-value of 0.158.

Quality of the evidence

Evidence originated from RCTs and the level of the quality of the evidence comparing rates of chronic pain for fixation versus no fixation in TEP repair started therefore at ‘High’. However, the quality of the evidence was downgraded with two levels for substantial methodological limitations of the studies (high Risk of Bias, for example due to unclear randomization process). The level of the quality of the evidence was further downgraded one level for substantial imprecision (low number of patients).

Recurrence (critical outcome)

Ayyaz 2015 reported 1 event of recurrence in the non-fixation group and no events in the mesh fixation group, five years post-surgery. The study of Buyukasik (2017) reported zero recurrence events in both groups.

Quality of the evidence

Evidence originated from RCTs and the level of the quality of the evidence comparing recurrence rates for fixation versus no fixation in TEP repair started therefore at ‘High’. However, the quality of the evidence was downgraded with two levels for substantial methodological limitations of the studies (high Risk of Bias, for example due to unclear randomization process). The level of the quality of the evidence was further downgraded two levels for substantial imprecision (very low number of events).

Operative time (other outcome)

Claus (2016) and Buyukasik (2017) reported data on operative time. The technique without fixation was less time-consuming compared to fixation, however, the difference was not statistically significant.

Evidence originated from RCTs and the level of the quality of the evidence comparing the amount of operative time for fixation versus no fixation in TEP repair started therefore at ‘High’. However, the quality of the evidence was downgraded one level for substantial methodological limitations of the studies (high Risk of Bias, for example due to uncertainty about intention to treat analysis and loss to follow up). The level of the quality of the evidence was further downgraded two levels for serious imprecision (low number of patients, very wide confidence intervals that crossed 0,0 indicating ambiguity between recommending and not recommending either the intervention or control)

Post-operative pain (other outcome)

Buyukasik (2017) reported post-operative pain (defined as pain prior to discharge). In the fixation group, the mean pains core (Numeric Rating Scale) was 1.9 (±1.6) and in the non-fixation group, the mean score was 1.3 (±1.2) with a p-value of 0,034

Quality of the evidence

Evidence originated from RCTs and the level of the quality of the evidence comparing rates of post-operative pain for fixation verus no fixation in TEP repair started therefore at ‘High’. However, the quality of the evidence was downgraded one level for substantial methodological limitations of the studies (high Risk of Bias, for example due to incomplete outcome data). The level of the quality of the evidence was further downgraded two levels for serious imprecision (low number of patients).

Smith (1999) reported that no statistically significant difference was observed between the two groups in chronic pain, but details were not reported.

Recurrence (important outcome)

Smith (1999) reported three events of recurrence in the stapled group and no events in the non-stapled group (p=0.09).

Operative time (other outcome)

Smith (1999) reported a duration of 30 minutes for both procedures.

Quality of the evidence

Evidence originated from one RCT and the level of the quality of the evidence started therefore at ‘High’. However, the quality of the evidence was downgraded with three levels for substantial methodological limitations of this one study (high Risk of Bias, for example due to unclear randomization process). The level of the quality of the evidence was further downgraded two levels for serious imprecision (one study, low number of patients).

3. What are appropriate types of mesh fixation in laparo-endopscopic (i.e. TEP and TAPP) inguinal/femoral hernia repair in adults?

A search using the PICO criteria yielded two systematic reviews (Antoniou, 2016; Shi, 2017) relevant for the subject of mesh fixation in laparoscopic inguinal hernia repair. Antoniou 2016 compared noninvasive and invasive mesh fixation in both TEP and TAPP hernia repair. The SR of Shi (2017) compared only mesh fixation using fibrin glue versus staple in TAPP repair. Therefore, we chose to include the study of Antoniou. One RCT (Boldo, 2008) cited in the SR of Shi (2017), but not in Antoniou (2016), was not added to the collection of Antoniou (2016), because they did not specify number of patients between the intervention and outcome groups.

Between two and ten staples or Tackers were used for mesh fixation. Absorbable sutures were used in three studies. One study included only patients subjected to bilateral her-nia repair (Moreno-Egea, 2014).

Table 1 Number of studies and patients for each non-penetrating mesh fixation com-pared to mechanical fixation

Evidence originated from RCTs and the level of the quality of the evidence comparing rates of chronic pain after traumatic and non-traumatic mesh fixation started therefore at ‘High’. However, the quality of the evidence was downgraded one level for some methodological limitations of the studies (Risk of Bias, for example due to possible selection bias). The level of the quality of the evidence was further downgraded two levels for serious imprecision (very few events and sample size <2000). We acknowledge the variety in types of inguinal hernia repair, but we did not downgrade for clinical heterogeneity. Instead, we reported results for the two types of operative techniques for inguinal hernia repair separately.

Recurrence (critical outcome)

Eight RCTs (n=774) reported recurrence rates (Figure 3). Both TEP and TAPP were used in four studies. In the group of patients that received traumatic mesh fixation a total of three patients reported a recurrence compared to four patients among those that received nontraumatic fixation (RR 0.86 (95% CI 0.20 to 3.69).

Quality of the evidence

Evidence originated from RCTs and the level of the quality of the evidence comparing recurrence rates after traumatic and nontraumatic mesh fixation started therefore at ‘High’. However, the quality of the evidence was downgraded two levels for serious imprecision (very few events and sample size <2000). We acknowledge the variety in types of inguinal hernia repair that were compared, but we did not downgrade for clinical heterogeneity. Instead, we reported results for the two types of operative techniques for inguinal hernia repair separately.

Operative time (other outcome)

Five studies (n=581) reported on operating time as outcome (Figure 4), two studies reported on TAPP and three studies reported on TEP. Mean operating time ranged from 39 to 73 minutes when mechanical fixation was used. When nontraumatic fixation was applied, the mean operating time ranged from 37 to 76 minutes. The mean difference was 3 minutes in favour of traumatic fixation, but this difference was not statistically significant different (CI -14.37 to 7.99). (SMD -0.35, 95% CI -1.25 to -0.54)

Quality of the evidence

Evidence originated from RCTs and the level of the quality of the evidence comparing operating time started therefore at ‘High’. However, the quality of the evidence was downgraded one level for considerable heterogeneity (minimal or no overlap of confidence intervals in studies reporting on the same operative technique and indicating either an effect or no effect, I2 statistic 85% and 98%).

Post-operative pain (other outcome)

Short-term pain assessment was inconsistently reported and the data of several studies were not suitable for use in meta-analysis (due to the reporting of median values and ranges). Five studies reported pain scores 24 to 48 hours after surgery. Four studies (n=342) showed comparable median scores (1 to 2 on a 10-point VAS) in both groups (Lau, 2005; Fortelny, 2012; Subwoncharoen, 2013; Tolver, 2013)). Only one study, OImi (2007), reported a more than two-fold higher pain score in the group receiving mechanical fixation (n=450) compared to the group receiving nontraumatic fixation (n=150) (5.3 points on a 10-point VAS versus 2 points).

Quality of the evidence

Evidence originated from RCTs and the level of the quality of the evidence comparing post-operative pain started therefore at ‘High’. However, the quality of the evidence was downgraded one level for substantial methodological limitations of the studies (high or unclear Risk of Bias, for example due to reporting bias and nondisclosed or present conflicts of interest or industry sponsoring). The quality of the evidence was further downgraded due to considerable heterogeneity (studies reporting on the same operative technique and indicating either an effect or no effect).

The working group decided that chronic pain and recurrence were crucial outcome measures for decision-making. The working group did not define the mentioned out-come measures beforehand, however, they used the definitions described in the studies.

Searching and selecting (Methods)

The information specialist from the Cochrane Centre in the Netherlands searched Med-line and Embase on April 11th, 2017 and the Cochrane Register on April 12th, 2017 for systematic reviews (SRs) and randomized controlled trials (RCTs) about inguinal hernias, without restrictions on publication date. All duplicates (including duplicates from the former search on the 30th of June, 2015) were removed. The search details can be found in the tab Acknowledgement.

Literature experts excluded studies that were clearly not relevant for answering clinical questions about inguinal hernias. Therefore, 66 SRs and 241 RCTs remained to be judged by the working group.

The working group selected 15 studies (SRs and RCTs) which could be relevant for the research questions about mesh fixation, based on title-abstract.

PICO 1

After reading full text, 12 studies were excluded for the search question about mesh fixation for TEP (see exclusion table in the tab Acknowledgement); finally, three studies (RCTs) were included for analysis (Ayyaz, 2015; Buyukasik, 2017; Claus, 2016).

Three studies were used for the literature analysis. The most important study character-istics and results were extracted from the RCTs. The most important study characteristics and results are shown in the evidence tables. The judgement of the individual study quality (Risk of Bias) is shown in the Risk of Bias tables.

PICO 2

After reading full text, all studies were excluded for the search question about mesh fixation for TAPP (see exclusion table in the tab Acknowledgement); Finally, one study from the former search (30th of June 2015) and described in the world guideline, was selected (Smith, 1999). One RCT was used for the literature analysis. The most important study characteristics and results were extracted from the RCT. The most important study characteristics and results are shown in the evidence tables. The judgement of the individual study quality (Risk of Bias) is shown in the Risk of Bias tables.

PICO 3

After reading full text, 14 studies were excluded for the search question about mesh fixation for TEP and TAPP (see exclusion table in the tab Acknowledgement); finally, one SR was included for analysis (Antoniou, 2016). This SR described 9 RCTs (4 about TEP, 5 about TAPP) and were used for the literature analysis. The most important study characteristics and results were extracted from the SRs or original studies (in case of missing information in the review). The most important study characteristics and results are shown in the evidence tables. The judgement of the individual study quality (Risk of Bias) is shown in the Risk of Bias tables.

Data extraction and analysis

The most important study characteristics and results were extracted from the SRs or original studies (in case of missing information in the review). The most important study characteristics and results are shown in the evidence tables. The judgement of the individual study quality (Risk of Bias) is shown in the Risk of Bias tables.

Relevant pooled and/or standardized effect measures were, if useful, calculated using Review Manager 5.3 (Cochrane Collaboration, Oxford, United Kingdom). If pooling re-sults was not possible, the outcomes and results of the original study were used as reported by the authors.

De working group did not define clinical (patient) relevant differences for the outcome measures. Therefore, we used the following boundaries for clinical relevance, if applicable: for continue outcome measures: RR<0.75 or >1.25 (GRADE recommendation) or Standardized mean difference (SMD=0.2 (little); SMD 0.5 (reasonable); SMD=0.8 (large). These boundaries were compared with the results of our analysis. The interpretation of dichotomous outcome measures is strongly related to context; therefore, no clinical relevant boundaries were set beforehand. For dichotomous outcome measures, the absolute effect was calculated (Number Needed to Treat (NNT) or Number Needed to Harm (NNH)).

Outcomes were measured at 0,5, 1, 2 and 5 years. However it is not clear how the mean pain score was calculated.

No measurement of the following outcome measures: SSI, postoperative pain, recurrence

Risk of Bias: high. No information available on randomization, allocation concealment blinding of patients, loss to follow up, intention-to-treat analysis.

Notes:

Prognostic balance between treatment groups is usually guaranteed in randomized studies, but non-randomized (observational) studies require matching of patients between treatment groups (case-control studies) or multivariate adjustment for prognostic factors (confounders) (cohort studies); the evidence table should contain sufficient details on these procedures.

Provide data per treatment group on the most important prognostic factors ((potential) confounders).

For case-control studies, provide sufficient detail on the procedure used to match cases and controls.

For cohort studies, provide sufficient detail on the (multivariate) analyses used to adjust for (potential) confounders.

Study reference

(first author, publication year)

Describe method of randomisation1

Bias due to inadequate concealment of allocation?2

(unlikely/likely/unclear)

Bias due to inadequate blinding of participants to treatment allocation?3

(unlikely/likely/unclear)

Bias due to inadequate blinding of care providers to treatment allocation?3

(unlikely/likely/unclear)

Bias due to inadequate blinding of outcome assessors to treatment allocation?3

(unlikely/likely/unclear)

Bias due to selective outcome reporting on basis of the results?4

(unlikely/likely/unclear)

Bias due to loss to follow-up?5

(unlikely/likely/unclear)

Bias due to violation of

intention to treat analysis?6

(unlikely/likely/unclear)

Buyukasik 2017

‘Closed envelop methods’;

Unlikely, identical closed envelopes were used

Not applicable, envelopes were picked during aneshesia of patient

Likely, however, randomization was done at time of mesh insertion

Likely

Unclear

Unclear

Unclear

Claus 2016

Computer generated however, group sizes were very unequal.

Unclear

Unclear

Unclear

Unclear

Unlikely

Unclear

Unclear

Ayyaz 2015

‘Lottery method’ into even and odd

Unclear

Unclear

Unclear

Unclear

Likely, only mean pain scores were reported despite follow-up at five different time points

Unclear

Unclear

Randomisation: generation of allocation sequences have to be unpredictable, for example computer generated random-numbers or drawing lots or envelopes. Examples of inadequate procedures are generation of allocation sequences by alternation, according to case record number, date of birth or date of admission.

Allocation concealment: refers to the protection (blinding) of the randomisation process. Concealment of allocation sequences is adequate if patients and enrolling investigators cannot foresee assignment, for example central randomisation (performed at a site remote from trial location) or sequentially numbered, sealed, opaque envelopes. Inadequate procedures are all procedures based on inadequate randomisation procedures or open allocation schedules.

Blinding: neither the patient nor the care provider (attending physician) knows which patient is getting the special treatment. Blinding is sometimes impossible, for example when comparing surgical with non-surgical treatments. The outcome assessor records the study results. Blinding of those assessing outcomes prevents that the knowledge of patient assignement influences the proces of outcome assessment (detection or information bias). If a study has hard (objective) outcome measures, like death, blinding of outcome assessment is not necessary. If a study has “soft” (subjective) outcome measures, like the assessment of an X-ray, blinding of outcome assessment is necessary.

Results of all predefined outcome measures should be reported; if the protocol is available, then outcomes in the protocol and published report can be compared; if not, then outcomes listed in the methods section of an article can be compared with those whose results are reported.

If the percentage of patients lost to follow-up is large, or differs between treatment groups, or the reasons for loss to follow-up differ between treatment groups, bias is likely. If the number of patients lost to follow-up, or the reasons why, are not reported, the Risk of Bias is unclea

Participants included in the analysis are exactly those who were randomized into the trial. If the numbers randomized into each intervention group are not clearly reported, the Risk of Bias is unclear; an ITT analysis implies that (a) participants are kept in the intervention groups to which they were randomized, regardless of the intervention they actually received, (b) outcome data are measured on all participants, and (c) all randomized participants are included in the analysis.

Authors conclude that it is not necessary to secure an appropriately placed 10 × 15-cm piece of mesh during a laparoscopic TAPP inguinal hernia repair.

Data for chronic pain not reported, but authors mention “Stapling the mesh made no statistically significant difference to the incidence of recurrence, port-site hernia, or chronic groin pain in this study”

Notes:

Prognostic balance between treatment groups is usually guaranteed in randomized studies, but non-randomized (observational) studies require matching of patients between treatment groups (case-control studies) or multivariate adjustment for prognostic factors (confounders) (cohort studies); the evidence table should contain sufficient details on these procedures.

Provide data per treatment group on the most important prognostic factors ((potential) confounders).

For case-control studies, provide sufficient detail on the procedure used to match cases and controls.

For cohort studies, provide sufficient detail on the (multivariate) analyses used to adjust for (potential) confounders.

Study reference

(first author, publication year)

Describe method of randomisation1

Bias due to inadequate concealment of allocation?2

(unlikely/likely/unclear)

Bias due to inadequate blinding of participants to treatment allocation?3

(unlikely/likely/unclear)

Bias due to inadequate blinding of care providers to treatment allocation?3

(unlikely/likely/unclear)

Bias due to inadequate blinding of outcome assessors to treatment allocation?3

(unlikely/likely/unclear)

Bias due to selective outcome reporting on basis of the results?4

(unlikely/likely/unclear)

Bias due to loss to follow-up?5

(unlikely/likely/unclear)

Bias due to violation of

intention to treat analysis?6

(unlikely/likely/unclear)

Smith 1999

Not reported

Unclear

Unclear

Unclear

Unlikely

Unclear

Unlikely

Unlikely

Randomisation: generation of allocation sequences have to be unpredictable, for example computer generated random-numbers or drawing lots or envelopes. Examples of inadequate procedures are generation of allocation sequences by alternation, according to case record number, date of birth or date of admission.

Allocation concealment: refers to the protection (blinding) of the randomisation process. Concealment of allocation sequences is adequate if patients and enrolling investigators cannot foresee assignment, for example central randomisation (performed at a site remote from trial location) or sequentially numbered, sealed, opaque envelopes. Inadequate procedures are all procedures based on inadequate randomisation procedures or open allocation schedules.

Blinding: neither the patient nor the care provider (attending physician) knows which patient is getting the special treatment. Blinding is sometimes impossible, for example when comparing surgical with non-surgical treatments. The outcome assessor records the study results. Blinding of those assessing outcomes prevents that the knowledge of patient assignement influences the proces of outcome assessment (detection or information bias). If a study has hard (objective) outcome measures, like death, blinding of outcome assessment is not necessary. If a study has “soft” (subjective) outcome measures, like the assessment of an X-ray, blinding of outcome assessment is necessary.

Results of all predefined outcome measures should be reported; if the protocol is available, then outcomes in the protocol and published report can be compared; if not, then outcomes listed in the methods section of an article can be compared with those whose results are reported.

If the percentage of patients lost to follow-up is large, or differs between treatment groups, or the reasons for loss to follow-up differ between treatment groups, bias is likely. If the number of patients lost to follow-up, or the reasons why, are not reported, the Risk of Bias is unclear.

Participants included in the analysis are exactly those who were randomized into the trial. If the numbers randomized into each intervention group are not clearly reported, the Risk of Bias is unclear; an ITT analysis implies that (a) participants are kept in the intervention groups to which they were randomized, regardless of the intervention they actually received, (b) outcome data are measured on all participants, and (c) all randomized participants are included in the analysis.

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Antoniou 2016

**data extracted from original study

SR and meta-analysis of RCTs

Literature search up to 4th of January 2015 (PubMed and the Cochrane Central Register of Controlled Trials)

Defines as the number of patients with adverse events related to the method of fixation (infectious complications, allergic or other reactions for tissue adhesives, acute neuralgia for mechanical mesh fixation)

One study (F) reported a more than two-fold higher pain score in the group receiving mechanical fixation (n=450) compared to the group receiving non-traumatic fixation (n=150) (5.3 points on a 10-point VAS versus 2 points)

Facultative:

Brief description of author’s conclusion: ‘’The use of bioglues may be supported as an alternative approsach to mechanical fixation in laparoscopic groin hernia repair without an increase in operative morbidity. Routine application cannot be supported until long-term results are available.’’

Sensitivity analyses: sub-groupanalyses were done to specify outcomes for TEP and TAPP

Heterogeneity: heterogeneity existed in the definition and measurement of end points.

Table of quality assessment for systematic reviews of RCTs and observational studies

An assessment of publication bias should include a combination of graphical aids (For example funnel plot, other available tests) and/or statistical tests (e.g., Egger regression test, Hedges-Olken). Note: If no test values or funnel plot included, score “no”. Score “yes” if mentions that publication bias could not be assessed because there were fewer than 10 included studies.

Sources of support (including commercial co-authorship) should be reported in both the systematic review and the included studies. Note: To get a “yes,” source of funding or support must be indicated for the systematic review AND for each of the included studies.